Abnormal heart rhythms and their treatment remain major public health threats in the United States. We will continue to investigate the changes in passive and active membrane properties in heart tissue that underly arrhythmogenesis and the mechanisms of action of antiarrhythmic drugs. Multiple microelectrode techniques of intracellular current application and transmembrane voltage recording will be employed in sheep cardiac Purkinje fibers, techniques that permit the selective control of numerous electrophysiologic variables and allow the direct assessment of the determinants of cardiac excitability. We will also continue to develop and utilize techniques by which intracellular ionic activities can be measured utilizing intracellular glass microelectrodes. We are particularly interested in studying the effects of toxic metabolites that accumulate in the ischemic myocardium, particularly lysophosphatidylcholine (LPC) which we have demonstrated has important electrophysiologic effects and which seems to be of importance in resistant clinical arrhythmias. We are also interested in the effects that important antiarrhythmic drugs have on membrane properties in general and on the alterations in these properties induced by LPC and similar compounds. Classifications of arrhythmogenesis and anti-arrhythmic drugs that are both electrophysiologically sound and clinically useful will continue to be developed. Computer modeling will be used to test theory experimentally and otherwise assist in data interpretation.